AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011

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1 195 AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011 Authors C. Hiemke 1, P. Baumann 2, N. Bergemann 3, A. Conca 4, O. Dietmaier 5, K. Egberts 6, M. Fric 7, M. Gerlach 6, C. Greiner 8, G. Gründer 9, E. Haen 10, U. Havemann-Reinecke 11, E. Jaquenoud Sirot 12, H. Kirchherr 13, G. Laux 7, U. C. Lutz 14, T. Messer 15, M. J. Müller 16, B. Pfuhlmann 17, B. Rambeck 18, P. Riederer 17, B. Schoppek 19, J. Stingl 20, M. Uhr 21, S. Ulrich 22, R. Waschgler 23, G. Zernig 24 Affiliations Key words consensus guidelines drug analysis pharmacokinetics psychotropic drugs reference ranges therapeutic drug monitoring therapeutic window Bibliography DOI /s Pharmacopsychiatry 2011; 44: Georg Thieme Verlag KG Stuttgart New York ISSN Correspondence C. Hiemke, PhD, Univ.-Prof. Department of Psychiatry and Psychotherapy University Medical Center, Mainz D Mainz Germany Tel.: +49/6131/ Fax: +49/6131/ Affiliation addresses are listed at the end of the article Introduction In psychiatry, around 130 drugs are now available which have been detected and developed during the last 60 years [ 54 ]. These drugs are effective and essential for the treatment of many psychiatric disorders and symptoms. Despite enormous medical and economic benefits, however, therapeutic outcomes are still far from satisfactory for many patients [5, 6, 396, 661 ]. Therefore, after having focused clinical research on the development of new drugs during more Abstract Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from strongly recommended to potentially useful. Evidence-based therapeutic reference ranges and dose related reference ranges were elaborated after an extensive literature search and a structured internal review process. A laboratory alert level was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrateand inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort. than 5 decades [521, 522 ], growing evidence suggests that improving the way the available medications are administered may bring substantial benefit to patients [45 ]. Evidence-based guidelines for optimum treatment have been published during the last decade [23, 46, 101, 204, 205, 221, 234, 254, 276, 284, 582, 585,748]. A valuable tool for tailoring the dosage of the prescribed medication(s) to the individual characteristics of a patient is therapeutic drug monitoring (TDM). The major reason to use TDM for the guidance of psychopharmacotherapy is the

2 196 Review considerable interindividual variability in the pharmacokinetic properties of the patient [ 524, 526 ]. At the very same dose, a more than 20-fold interindividual variation in the medication s steady state concentration in the body may result, as patients differ in their ability to absorb, distribute, metabolize and excrete drugs due to concurrent disease, age, concomitant medication or genetic peculiarities [61, 94, 310, 311, 334, 335, 374 ]. Different formulations of the same medication may also influence the degree and temporal pattern of absorption and, hence, medication concentrations in the body. TDM uses the quantification of drug concentrations in blood plasma or serum to titrate the dose of individual patients so that a drug concentration associated with highest possible probability of response and tolerability and a low risk of toxicity can be obtained. Moreover, TDM has the possible and widely unexploited potential to improve cost-effectiveness of psychopharmacotherapy [527, 660 ]. For a considerable number of psychopharmacologic compounds, the quantification of the medications plasma concentration has become clinical routine for dose adjustment. Clear evidence of the benefits of TDM has been given for tricyclic antidepressants, a number of old and new antipsychotic drugs and for conventional mood stabilizing drugs [51, 459, 505 ]. For lithium, TDM has become a standard of care due to its narrow therapeutic range [133, 395 ]. The benefits of TDM regarding the optimization of pharmacotherapy, however, can only be obtained if the method is adequately integrated into the clinical treatment process. Current TDM use in psychiatric care is obviously suboptimal [ 134, 700, 742 ]. Similar to other medical disciplines, systematic studies have demonstrated that the inappropiate use of TDM is widespread. Inappropriate TDM testing wastes laboratory resources and also bears the risk that misleading results will adversely influence clinical decision making [122 ]. A study on the clinical use of TDM for tricyclic antidepressants in psychiatric university hospital settings showed that between 25 and 40 % of the requests for TDM were inappropriate and the interpretation of the results led to about 20 % of inappropriate therapeutic adjustments [700, 742 ]. Other typical errors were absence of steady-state conditions and transcription errors on the request form [ 700,743 ]. Studies on TDM for antidepressant and mood stabilizing drugs further specified the information on the inappropriate use of TDM [420, 421 ]. Against this background, the TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued best practice guidelines for TDM in psychiatry in 2004 [ 51 ]. These guidelines were widely accepted by many laboratories and practicing clinicians. They have been cited more than 200 times in the literature and were translated into German [ 312 ] and French [ 50 ]. Moreover, they were summarized for depression [ 52 ]. The AGNP-TDM consensus guidelines have also been implemented in recent international guidelines on the treatment of mental diseases [ 582 ]. Since 2004, knowledge on TDM has advanced significantly. New psychotropic medications have been introduced which are also candidates for TDM. The TDM group of the AGNP therefore decided to prepare an updated version of their guidelines. Objectives of this Consensus Document This document addresses topics related to the theory and practice of TDM in psychiatry. The first part deals with theoretical aspects of monitoring drug plasma concentrations. The second part defines indications for TDM and gives reference drug plasma concentrations for dose optimization. The third part describes the best practice of the process of TDM, which starts with the request and ends with the clinical decision to either continue or change the pre-tdm pharmacotherapy. Aiming to optimise the practice of TDM the following topics were addressed: de finition of indications to utilize TDM in psychiatry de finition of graded levels of recommendations to use TDM definition of therapeutic reference ranges ( therapeutic windows ) and dose-related reference ranges that laboratories can quote and clinicians can use to guide the psychopharmacotherapy de finition of alert levels for laboratories to warn the treating physician when plasma concentrations are considered to be too high and potentially harmful recommendations and help for interpretative services recommendations concerning the combination of TDM with pharmacogenetic tests Preparation of the Consensus Document The updated consensus guidelines were prepared by the interdisciplinary TDM group of the AGNP consisting of clinical psychiatrists, pharmacologists, biochemists, pharmacists and chemists from academic and non academic hospitals and institutions of Germany, Switzerland, Austria and Italy, who have been involved for many years in the development and implementation of TDM for psychotropic medications in everyday clinical practice. The experts compiled information from the literature and worked out the present best practice guidelines aiming at promoting the appropriate use of TDM in psychiatry. Because TDM is widely used in daily clinical practice for antidepressant, antipsychotic and mood stabilizing drugs, these 3 pharmacologic classes are extensively represented in the present guidelines. Anxiolytic and hypnotic drugs, antidementia drugs, drugs for treatment of substance abuse related disorders and other psychotropic drugs are also candidates for TDM and are thus covered in the present guidelines. In special situations, the measurement of drug plasma concentrations can be helpful for any drug. Many patients are simultaneously treated for neurologic and psychiatric disorders. Therefore, the updated guidelines also contain information on anticonvulsant and antiparkinson drugs which are also more or less well established candidates for TDM [481, 499 ] and were thus extended from 65 psychiatric drugs in 2004 [ 51 ] to 128 neuropsychiatric drugs at present. Data published in the AGNP consensus guidelines 2004 [ 51 ] and other guidelines and recommendations for TDM of primarily antidepressant and antipsychotic drugs [317, 400, , 504, 505 ] were initially used as the basis for this update. An extensive literature search was conducted, primarily in MEDLINE, to identify TDM-related information for the surveyed 128 neuropsychiatric drugs. The search concentrated on reports on optimum plasma concentrations, dose related drug plasma concentrations, cytochrome P450 substrate, inducer and inhibitor properties and on ratios of concentrations of drug metabolites to parent drugs. Relevant reports were also searched by hand in pharmacologic and clinical chemical journals dealing with TDM. Over articles were assessed and

3 197 analysed. Extracted data on reference ranges were listed in tables by 7 authors (CH, EH, CG, BR, PR, HK). Results of the literature search and analyses were sent out for review to 20 members of the TDM group with inclusion of a checklist how to extract and analyse the data. An internet based and passwordprotected platform was built up for the reviewers to have access to relevant articles. The reviewers protocols and commentaries were distributed to all authors of these guidelines. Final decisions on data reported in this document were made during 2 consensus conferences and by communication. Consensus making also included definitions of reference ranges, alert levels and graded levels of recommendations to utilize TDM. Theoretical Aspects of TDM in Psychiatry Pharmacokinetics, metabolism and pharmacogenetics of neuropsychiatric drugs Most psychotropic drugs share a number of pharmacokinetic characteristics good absorption from the gastrointestinal tract within plasma concentrations reaching a maximum within 1 6 h highly variable first-pass metabolism (systemic bioavailability ranging 5 90 %) fast distribution from plasma to the central nervous system with 2- to 40-fold higher levels in brain than in blood high apparent volume of distribution (about L/kg) low trough plasma concentrations under steady-state (about ng/ml for psychoactive drugs and up to 20 μg/ml for neurological drugs) slow elimination from plasma (half-life h) mainly by hepatic metabolism linear pharmacokinetics at therapeutic doses which has the consequence that doubling the daily dose will result in a doubling of the plasma level low renal excretion with small effect of renal insufficiency on the plasma concentrations of parent drug and active meta bolites cytochrome P450 (CYP) and UDP-glucuronosyltranferases as major metabolic enzyme systems There are, however, numerous exceptions. For example, venlafaxine, nefazodone, trazodone, tranylcypromine, moclobemide, quetiapine, rivastigmine and ziprasidone display short (about 2 10 h) elimination half-lives, whereas aripiprazole and fluoxetine have long elimination half-lives (72 h for aripiprazole and 3 15 days for fluoxetine, taking into account its active metabolite norfluoxetine). Amisulpride, milnacipran, memantine, gabapentin, or sulpiride are not or only poorly metabolised in the liver but also mainly excreted renally. Paroxetine exhibits non-linear pharmacokinetics, due to the inhibition of its own metabolism by a metabolite which is irreversibly bound to the enzyme (mechanism based inhibition) resulting in its inactivation [ 69 ]. Many psychotropic drugs are used as racemic compounds, and their enantiomers differ markedly in their pharmacology, metabolism and pharmacokinetics [53, 605 ]. So far however, methadone, methylphenidate and flupentixol are at present the only racemic psychotropic compounds for which TDM of the enantiomers has been introduced [39, 189 ]. The active principles of racemic methadone and fluoxetine are (R)-methadone and cis-(z)-flupentixol, respectively. For research projects and other special situations, stereoselective analysis should be considered, e. g., for citalopram, fluoxetine, reboxetine, venlafaxine, paliperidone or amitriptyline metabolites. Most psychotropic drugs undergo phase-i metabolism by oxidative (e. g., hydroxylation, dealkylation, oxidation to N-oxides, S-oxidation to sulfoxides or sulfones), reductive (e. g., carbonyl reduction to secondary alcohols) or hydrolytic reactions, dealkylation, oxidation to N-oxides, carbonyl reduction to secondary alcohols or S-oxidation to sulfoxides or sulfones. The phase-i reactions are predominantly catalysed by cytochrome P450 (CYP) enzymes which comprise more than 200 isoenzymes. The most important isoenzymes for psychotropic medications are CYP1A2, CYP2B6, CYP2D6, CYP2C9, CYP2C19 and CYP3A4/5 ( Table 1 ) [ ]. In general, phase-i reactions introduce a polar functional group that enables a phase-ii conjugation reaction with highly polar molecules such as glucuronic or sulphuric acid. For psychotropic compounds possessing functional groups in the parent compound, glucuronidation of a hydroxyl group (for example oxazepam or lorazepam) or an N-H group (for example olanzapine) may represent the essential metabolic pathway. In addition, tertiary amine groups can be conjugated with the formation of quaternary ammonium glucuronides. Actually, phase II enzymes are poorly characterised with regard to substrate specificity, and there is much overlap between the isozymes regarding affinity for substrates [143 ]. Other enzymatic systems may also be involved, such as ketoaldehyde oxidases [ 43 ], which have been shown to reduce ziprasidone to its dihydro-derivative [ 58 ] or naltrexone to naltrexol [ 92 ], or MAO-A and MAO-B, which deaminate citalopram stereoselectively to an apparently inactive acidic metabolite [562 ]. Drugs are metabolised mainly in the liver and, to a minor degree, in extrahepatic tissues such as the intestinal mucosa or the brain [59, 238, 444 ]. Inter- and intra-individual differences in plasma concentrations of psychotropic drugs (i. e., the pharmacokinetic variability) are caused by different activities of drug-metabolising enzymes. The enzyme activity may decrease with age [ 374 ] and can be modified by renal and hepatic diseases. Gender differences have been reported for psychotropic drugs, but the findings are inconsistent and the clinical relevance is not clear [7 9, 608 ]. For a number of psychoactive drugs, metabolites actively contribute to the overall clinical effect of the parent compound. For this reason, TDM must include the quantification of active metabolites, e. g., in the case of clomipramine (norclomipramine), doxepin (nordoxepin), fluoxetine (norfluoxetine) or risperidone (9-hydroxyrisperidone). For drugs like sertraline or clozapine, the clinical relevance of their metabolites norsertraline and norclozapine, respectively, is still a matter of debate. The analysis of pharmacologically inactive metabolites, however, may give useful information on the metabolic state of the patient or on his/her compliance [105, 569 ]. Table 2 shows the normal ratios of concentrations of metabolites to parent drugs. Calculated ranges contain 68 % of the ratios expected under standard dosages, i. e., ratios within the range of the mean ± 1 SD assuming normal distribution. A ratio above or below the normal ratio ( Table 2 ) can indicate problems of drug adherence [ 546 ] or metabolic abnormalities due to a genetic variation [157, 159, 350, 592 ] or a drug-drug interaction. Spina and coworkers [ 618 ] have shown this for the conversion of 2-hydroxydesipramine to desipramine. With regard to drug-drug interactions, ratios increase if the enzymatic conversion of the parent medication is induced by concurrent psychotropic or non-psychotropic medications or pharmacokinetically relevant activities such as smoking ( Table 3 ). Other co-medications and food

4 198 Review Table 1 Psychopharmacologic medications and enzymes involved in their metabolism. Drug (active metabolite) Enzymes Reference Acamprosate not involved (not metabolized) [ 578 ] Agomelatine CYP1A2, CYP2C19 [ 78 ] Amantadine merely involved (90 % excreted unmetabolized) [ 24 ] Alprazolam CYP3A4/5 [ 17, 496 ] Amisulpride merely involved (more than 90 % is excreted [ 566 ] unmetabolized via the kidney) Amitriptyline and amitriptyline oxide (amitriptyline, nortriptyline) CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 [ 90, 650, 713 ] Aripiprazole (dehydroaripiprazole) CYP2D6, CYP3A4 [ 306, 701 ] Asenapine Glucuronosyltransferase and CYP1A2 [ 707 ] Atomoxetine CYP2D6 [ 446 ] Benperidol unclear [ 589 ] Benserazide hydroxylation, COMT [ 347 ] Biperiden hydroxylation [ 628 ] Bromocriptine CYP3A4 [ 513 ] Bromperidol CYP3A4 [ 230, 633, 645, 736 ] Brotizolam CYP3A4 [ 655 ] Buprenorphine (norbuprenorphine) CYP2C8, CYP3A4 [ 79, 454 ] Bupropion (hydroxybupropion) CYP2B6 [ 309 ] Buspirone CYP3A4 [ 416 ] Cabergoline hydrolysis, CYP3A4 [ 167 ] Carbidopa unknown metabolic pathways 1/3 unmetabolized [ 575 ] Carbamazepine, CBZ (CBZ-10,11-epoxide)* CYP1A2, CYP2B6, CYP2C8, CYP3A4/5 [ 360, 497 ] Chlorpromazine CYP1A2, CYP2D6 [ 724 ] Citalopram CYP2C19, CYP2D6, CYP3A4 [ 97, 227, 739 ] Clomipramine (norclomipramine) CYP1A2, CYP2C19, CYP2D6, CYP3A4 [ 244 ] Clomethiazol CYP2A6, CYP2B6, CYP3A4 [ 116 ] Clozapine CYP1A2, CYP2C19, CYP3A4 [ 334, 487 ] Desipramine CYP2D6 [ 244 ] Diazepam (nordazepam, oxazepam, temazepam) CYP2B6, CYP2C19, CYP3A4 [ 228, 704 ] Dihydroergocryptine CYP3A4 [ 19, 162 ] Diphenhydramine CYP2D6 [1 3 ] Disulfiram CYP1A2, CYP2B6, CYP2E1, CYP3A4 [ 412 ] Donepezil CYP2D6, CYP3A4 [ 681 ] Dothiepin = Dosulepin CYP2C19, CYP2D6 [ 740 ] Doxepin (nordoxepin) CYP2C9, CYP2C19, CYP2D6 [ 295, 365 ] Duloxetine CYP1A2, CYP2D6 [ 405 ] Entacapone Glucuronosyltransferase [ 387 ] Escitalopram CYP2C19, CYP2D6, CYP3A4 [ 662, 697 ] Fluoxetine (norfluoxetine) CYP2B6, CYP2C9, CYP2C19, CYP2D6 [ 404, 588 ] Flupenthixol CYP2D6 [ 148, 365 ] Fluphenazine CYP2D6 [ 746 ] Fluvoxamine CYP2D6, CYP1A2 [ 354, 450 ] Galantamine CYP2D6, CYP3A4 [ 34 ] Gabapentin unmetabolized renal excretion [ 77 ] Haloperidol CYP2D6, CYP3A4 [ 93, 645 ] Iloperidone CYP2D6, CYP3A4 [ 106 ] Imipramine (desipramine) CYP1A2, CYP2C19, CYP2D6, CYP3A4 [ 244, 413 ] Lamotrigine Glucuronosyltransferase, CYP2A6 [ 121 ] Levodopa Dopadecarboxylase, COMT, MAO [ 575 ] Levomepromazine CYP1A2, CYP2D6 [ 36 ] Levomethadon CYPC19, CYP2B6, CYP3A4, CYP2D6 [ 145 ] Lisuride CYP3A4, CYP2D6 [ 539 ] Lithium no metabolism, renal clearance [ 256, 619 ] Lorazepam Glucuronosyltransferase [164, 196 ] Maprotiline CYP2D6, CYP1A2 [ 86 ] Melatonin CYP1A2 [ 296 ] Memantine merely metabolized [ 251 ] Methadone CYP2B6, CYP2C19, CYP3A4, CYP2D6 [ 145 ] Methylphenidate Carboxylesterase 1 [ 468 ] Mianserine CYP2D6, CYP1A2, CYP3A4 [ 379 ] Midazolam CYP3A4 [ 220 ] Milnacipran no CYP related metabolism [ 495, 533 ] Inhibition of enzymes indicated in bold will significantly increase the plasma concentrations of the drug, induction (CYP1A2, CYP3A4) will lead to decreased plasma concentrations (See Table 2 ). Prepared by CH, reviewed and supplemented by EJS

5 199 Table 1 Psychopharmacologic Continued. medications and enzymes involved in their metabolism. Drug (active metabolite) Enzymes Reference Mirtazapine CYP3A4, CYP1A2, CYP2B6, CYP2D6 [ 397, 630 ] Moclobemide CYP2C19, CYP2D6 [ 255 ] Modafinil Amide hydrolysis, CYP3A4 [ 561 ] Naltrexone Aldoketoreductase AKR1C4 [ 92 ] Nortriptyline CYP2D6 [ 385, 485, 687 ] Olanzapine N-Glucuronosyltransferase, Flavin monoxigenase, [ 107 ] CYP1A2, CYP2D6 Opipramol unclear Paliperidone ( = 9-Hydroxyrisperidone) 60 % excreted unmetabolized, different pathways [161] Paroxetine CYP1A2, CYP2D6, CYP3A4 [ 209, 349, 691 ] Perazine CYP1A2, CYP2C19, CYP3A4, Flavin monoxigenase [ 629,725 ] Pergolide CYP3A4 [ 731 ] Perphenazine CYP1A2, CYP2C19, CYP2D6, CYP3A4 [ 12, 77, 168, 486 ] Pregabalin unmetabolized renal excretion [ 77 ] Piripedil demethylation, p-hydroxylation, and N-oxidation [ 168 ] Pimozide CYP1A2, CYP3A4 [ 171 ] Pramipexole not metabolized [ 62 ] Promazine CYP1A2, CYP2C19, CYP3A4 [ 726 ] Promethazine CYP2D6 [ 465 ] Quetiapine CYP3A4, CYP2D6 [3 8 ] Rasagiline CYP1A2 [ 277 ] Reboxetine CYP3A4 [ 307, 716 ] Risperidone (9-Hydroxyrisperidone) CYP2D6, CYP3A4 [ 732 ] Ropinirole CYP1A2 [ 357 ] Rotigotine Glucuronosyltransferase, several other unknown pathways [115] Selegiline CYP2B6 [6 0 ] Sertindole CYP3A4, CYP2D6 [ 729 ] Sertraline CYP2B6, CYP2C19, CYP2C9, CYP2D6 [ 482, 705 ] Thioridazine CYP1A2, CYP2C19, CYP2D6, CYP3A4 [ 648, 714 ] Tiapride mainly not metabolized [ 477 ] Tolcapone Glucuronosyltransferase [ 387 ] Trimipramine (nortrimipramine) CYP2C19, CYP2D6, CYP2C9 [ 187 ] Tranylcypromine monoamine oxidase, unclear [ 37 ] Trazodone CYP3A4, CYP2D6 [ 268, 567 ] Valproic acid Glucuronosyltransferase, CYP2A6, CYP2B6, CYP2C9, [ 641 ] beta-oxidation Venlafaxine (O-desmethylvenlafaxine) CYP2C19, CYP2D6, CYP3A4 [ 217, 434 ] Zaleplone Aldehyde oxidase, CYP3A4 [ 554 ] Ziprasidone CYP3A4, Aldehyde oxidase [58, 519 ] Zolpidem CYP1A2, CYP2C9, CYP3A4 [ 698 ] Zopiclone CYP2C8, CYP3A4 [ 57, 659 ] Zotepine CYP1A2, CYP2D6, CYP3A4 [ 596 ] Zuclopenthixol CYP2D6 [ 330 ] Inhibition of enzymes indicated in bold will significantly increase the plasma concentrations of the drug, induction (CYP1A2, CYP3A4) will lead to decreased plasma concentrations (See Table 2 ). Prepared by CH, reviewed and supplemented by EJS which inhibit metabolic enzymes may decrease the ratio. Table 3 summarizes drugs that are inhibitors or inducers of CYP enzymes and thus may lead to clinically relevant pharmacokinetic drugdrug interactions. Pharmacogenetic aspects The clinical importance of pharmacogenetic factors in the pharmacokinetics and pharmacodynamics of psychoptropic drugs is increasingly recognised [ 156, 199, 457 ]. Drug-metabolising enzymes, especially CYP isoenzymes, exhibit genetic variability [ ]. When the frequency of a deviation in the alleles is at least 1 % of the population, it is considered a genetic polymorphism. The number of active alleles in a gene determines how much of the enzyme is expressed (phenotype). Poor metabolisers (PM) lack functional alleles. Intermediate metabolisers (IM) are either genetically heterozygous, carrying an active and an inactive allele (or an allele with reduced activity) or have 2 alleles with reduced activity. Extensive metabolisers (EM) are wildtype with 2 active alleles, and ultra-rapid metabolisers (UM) have an amplification of functional alleles [ 66 ]. Genetic polymorphisms of drug-metabolising enzymes may be clinically important, because unexpected adverse reactions and toxicity may occur in PM due to increased plasma concentrations and non-response may occur in UM due to subtherapeutic plasma concentrations [160 ]. Prodrugs are activated by metabolism such as codeine by CYP2D6 to morphine or clopidogrel by CYP2C19 to 2-oxoclopidogrel. PM patients will not be able to produce pharmacologically active metabolites. Other enzyme systems such as UDP-glucuronosyltransferases also display genetic polymorphism [ 155 ], but their clinical relevance in pharmacopsychiatry is unclear. CYP genotyping methods are becoming more and more available, and guidelines have been published for their use in clinical practice [675 ]. The functional significance of many genotypes,

6 200 Review Table 2 Ranges of metabolite-to-parent concentration ratios for psychopharmacologic medications. Reported ranges contain 68 % of ratios determined under normal conditions in the blood of patients or healthy subjects. Drug Metabolite Ratios of concentrations metabolite: parent drug (Mean SD Mean + SD) Reference Amitriptyline Nortriptyline* (n = 83) [ 545 ] Aripiprazole Dehydroaripirazole(*) [ 306, 368, 452 ] PM of CYP2D6: 0.2 Bromperidol Reduced bromperidol (n = 31) [ 609, 633 ] Buprenorphine Norbuprenorphine (n = 5) [ 383 ] Bupropion Hydroxybupropion 5 47 (24 h, n = 9) [ 152, 253, 336 ] 6 30 (12 h, n = 9) Buspirone 6-Hydroxybuspirone (n = 20) [ 178 ] Carbamazepine Carbamazepine-10,11-epoxide (n = 14) [ 338 ] Citalopram N-Desmethylcitalopram (n = 2 330) [ 549 ] Clomipramine Norclomipramine* (n = 115) [545] Clozapine Norclozapine(*) nonsmokers (n = 98) [ 140, 308, 500 ] smokers (n = 198) Dothiepin Nordothiepin (n = 50) [ 325 ] Doxepin Nordoxepin (n = 12) [ 172, 363 ] PM CYP2C19: 1.8 (n = 4) PM CYP2D6: 0.8 (n = 6) Escitalopram N-Demethylescitalopram (n = 243) [ 548 ] Fluoxetine Norfluoxetine* (n = 334) [ 545 ] Fluvoxamine Fluvoxamino acid (n = 49) [ 237 ] Haloperidol Reduced haloperidol mean 0.6 [ 673 ] Imipramine Desipramine (n = 14) [ 95, 96, 632 ] PM CYP2D6 4.1 (n = 2) Maprotiline Desmethylmaprotiline (n = 76) [ 699 ] PM CYP2D6 4.9 Mianserin N-Desmethylmianserin (n = 182) [ 545 ] Mirtazapine N-Desmethylmirtazapine (n = 100) [ 591 ] Moclobemide Moclobemide N-oxide (n = 6) [ 291 ] Olanzapine N-Demethylolanzapine non smokers: [ 602 ] (n = 76) smokers: (n = 69) Perazine Desmethylperazine (n = 27) [91] Perphenazine N-Dealkylperphenazine (n = 54) [ 637 ] Quetiapine Norquetiapine (n = 25) [ 723 ] (calculated for 400 mg) Reboxetine O-Desethylreboxetine < 0.1 [ 484 ] Risperidone 9-Hydroxyrisperidone* EM or IM CYP2D6: [ 159, 677 ] PM CYP2D6: 1 Risperidone depot 9-Hydroxyrisperidone* EM: [ 469 ] Sertindole Dehydrosertindole (n = 6) [ 729 ] 1.0 in PM of CYP2D6 Sertraline Norsertraline (n = 348) [546] Trazodone m-chlorophenylpiperazine (mcpp) (total range) [328] Trimipramine Nortrimipramine* (n = 17) [ 142 ] Venlafaxine O-Desmethylvenlafaxine* N-Desmethylvenlafaxine EM or IM CYPD26: PM CYP2D6: 0.3 UM CYP2D6: > [ 592 ] *pharmacologically active metabolite, (*) active metabolite in vitro but unclear under in vivo conditions When SD values of ranges of ratios (SD ratio) were not reported in the literature, SD ratios were calculated in accordance with Gaussian s law for the propagation of errors: SD ratio = [(SD parent drug x mean metabolite)+(sd metabolite x mean parent drug)]/(mean metabolite) 2 Prepared by CH, reviewed by Sonja Brünen, Christiane Knoth, Elnaz Ostad Haji and Viktoria Stieffenhofer however, is unclear. For some enzymes, a genetic polymorphism is not clearly demonstrated despite the fact that they display a wide interindividual variability in their activity. Therefore it may be advantageous to use phenotyping methods with probe drugs such as caffeine for CYP1A2, omeprazole for CYP2C19, dextromethorphan for CYP2D6, or midazolam for CYP3A4/5 [403, 643 ]. Phenotyping measures the metabolic situation of the patient at the moment of the test, and allows to follow its evolution. The measurement, however, may be influenced by environmental factors such as smoking or comedications [201, 601, 749]. The clear advantage of genotyping is that it represents a trait marker and that its result is not influenced by environmental factors. It can be carried out in any situation and its result has a lifetime value.

7 201 Table 3 Inhibitors and inducers of enzymes involved in the metabolism of drug. Inhibiting drugs Inhibited enzymes Inducing drugs Induced enzymes Amiodarone CYP2C9, CYP2D6, CYP3A4 Carbamazepine CYP1A2, CYP2B6, CYP2C9, CYP3A4 Bupropion CYP2D6 Dexamethason CYP2C9, CYP3A4 Bromocriptine CYP3A4 Efavirenz CYP2B6, CYP3A4 Chinidine CYP2D6 Ethanol CYP2E1 Cimetidin CYP1A2, CYP2D6, CYP3A4 Ginkgo biloba CYP2C19 Ciprofloxacin CYP1A2 Isoniazide CYP2E1 Clarithromycin CYP3A4 St. John s wort CYP2C19, CYP3A4 Clopidogrel CYP2B6 Oxybutynin CYP3A4 Disulfiram CYP2E1 Phenobarbital CYP2C9, CYP2C19, CYP3A4 Duloxetine CYP2D6 Phenytoin CYP2B6, CYP2C9, CYP2C19, CYP3A4 Enoxacin CYP1A2 Primidon CYP2C9, CYP2C19, CYP3A4 Erythromycin CYP3A4 Smoke CYP1A2 Esomeprazole CYP2C19 Rifabutin CYP3A4 Felbamate CYP2C19 Rifampicin CYP1A2, CYP2B6, CYP2C9, CYP2C19 Fluconazole CYP2C19, CYP2C9, CYP3A4 Ritonavir CYP3A4, CYP2C9, CYP3A4 (high dose) Fluoxetine and norfluoxetine CYP2D6, CYP2C19 Fluvoxamine CYP1A2, CYP2C9, CYP2C19, CYP3A4 Indinavir CYP3A4 Isoniazid CYP1A2, CYP2A6, CYP2C19, CYP3A4 Itraconazol CYP2B6, CYP3A4 Ketoconazol CYP3A4 Levomepromazine CYP2D6 Melperone CYP2D6 Metoclopramide CYP2D6 Metoprolol CYP2D6 Miconazol CYP2C9, CYP2C19 Mifepriston CYP3A4 Moclobemide CYP2C19, CYP2D6 Nelfinavir CYP3A4 No rfloxacine CYP1A2 Omeprazole CYP2C19 Paroxetine CYP2D6 Perazine CYP1A2 Pergolide CYP2D6 Perphenazin CYP2D6 Propafenon CYP1A2, CYP2D6 Propranolol CYP2D6 Ritonavir CYP2D6, CYP3A4 Saquinavir CYP3A4, CYP2C9 Troleandomycin CYP3A4 Valproate CYP2C9 Verapamil CYP3A4 Voriconazol CYP2C9, CYP3A4 Combination of psychoactive drugs with these inhibitors or inducers can lead to clinically relevant drug-drug interactions ( or ) Prepared by CH, reviewed by EJS Recent investigations indicate that the drug efflux transporter P-glycoprotein (P-gp) in the intestinal mucosa and blood-brainbarrier is also relevant for the pharmacokinetic variability of psychotropic medications [ 1 ]. This protein, a member of the ATP-cassette binding (ABC) transporter protein family, is encoded by the multidrug resistance gene ( MDR1 ; ABCB1 ). It displays a genetic polymorphism, but as yet, mainly genotyping but not phenotyping (e. g., with digoxin) is more commonly used [ 129, 183, 210, 389 ]. Genetic polymorphism of P-gp may be of the same considerable clinical relevance as has been demonstrated for drug-metabolizing enzymes. For antidepressant drugs that are substrates of P-gp, a genotype dependent association of drug response was found [668, 669 ]. Both plasma concentrations of quetiapine and its clinical effectiveness have been shown to depend on the P-gp genotype of patients suffering from schizophrenia [ 470 ]. With regard to the occurrence of wanted or unwanted clinical effects of psychoactive drugs, some first reports suggest the influence of the genetic polymorphism of P-gp [279, 560 ]. However, further research is needed to evaluate the clinical relevance of the genetic polymorphisms of drug transporters. Dose and drug concentration in blood In most situations that use TDM for dose optimization, drugs are administered in a series of repeated doses to attain a steadystate concentration within a given therapeutic reference range. Steady-state is attained when the rate of medication input equals the rate of medication loss, i. e., approximately after 4 times the elimination half life. With multiple dosing, 94% of the steady state are achieved after 4 and 97% after 5 elimination half-lives. For more than 90 % of all psychoactive medications, such a steady-state is reached within 1 week of maintenance

8 202 Review Table 4 Total clearance (Cl t ), bioavailability (F), dosing intervals (τ) and factors (C/D low and C/D high ) for calculation of dose-related plasma concentrations (C/D) for psychotropic drugs. Drug n Cl t SD Cl t + SD [ml/min] F τ [h] C/D low [ng/ml/mg] C/D high [ng/ml/mg] Antidepressant drugs Amitriptyline [ 165 ] Amitriptyline oxide [ 384 ] Bupropion [ 665 ] Citalopram [ 616 ] Clomipramine [ 198 ] Desipramine [ 2 ] Desvenlafaxine [ 520 ] Dothiepin = Dosulepin [ 740 ] Doxepin [ 100 ] Duloxetine [ 600 ] Escitalopram [ 607 ] Fluoxetine n. r [ 18 ] Fluvoxamine [ 163 ] Imipramine n. r [ 100 ] Maprotiline [ 415 ] Mianserin n. r [ 137 ] Mirtazapine [ 651 ] Nordoxepin [ 445 ] Nortriptyline n. r [ 664 ] Paroxetine [ 213 ] Reboxetine n. r [ 141 ] Sertraline 11 (m) 11 (f) (m) (f) Reference Trazodone [ 473 ] Trimipramine [ 165, 364 ] Venlafaxine O-Desmethylvenlafaxine Antipsychotic drugs Amisulpride [ 566 ] Asenapine n. r [ 707 ] Aripiprazole [ 417 ] Benperidol [ 589 ] Bromperidol [ 390 ] Chlorpromazine [ 738 ] Chlorprothixene [ 534 ] Clozapine [ 128, 176, 332 ] Flupentixol [ 348 ] Fluphenazine decanoate [ 197 ] Haloperidol [ 123 ] Haloperidol decanoate Melperone [ 83 ] Levomepromazine [ 149 ] Olanzapine [ 67 ] Paliperidone n. r [ 161 ] Perphenazine [ 195 ] Pimozide [ 581 ] Quetiapine [ 7, 435 ] Risperidone, oral active moiety Risperidone, depot n. r active moiety active moiety 0.55 active moiety Sertindole [ 728 ] Supiride [ 717 ] Thiordazine [ 117 ] Zotepine [ 642 ] Ziprasidone SPC Zuclopenthixol [ 337 ] SPC: Summary of product characteristics; n.r.: not reported; active moiety: risperidone plus 9-hydroxyrisperidone; n: number of individuals; SD: standard deviation Dose related ranges are obtained by multiplying C/D low and C/D high by the dose. Drugs listed in Table 5 were not included in this table, when clearance data were not available from the literature. Prepared by EH and CG, reviewed and supplemented by CH [ 565 ] [ 372 ] [ 123 ] [ 159 ] [ 606 ]

9 203 Table 4 Total clearance (Cl t ), bioavailability (F), dosing intervals (τ) and factors (C/D low and C/D high ) for calculation of dose-related plasma concentrations (C/D) Table for psychotropic 4 Continued. drugs. Drug n Cl t SD Cl t + SD [ml/min] dosing. The dose required to attain a steady-state concentration of a drug in plasma can be calculated if the dosing interval (τ), the clearance (Cl) and the bioavailability (F) for the drug in a particular patient are known. The calculation is based on the direct correlation of the drug dose D e (constant dose per day at steady-state) to its blood concentration c, with the total clearance of the drug (Cl t ) being the correlation coefficient: D e = DxF/τ = c x Cl t Based on this information it is possible to calculate the dose-related plasma concentration of a drug that may be expected in blood specimens of patients under medication with a given dose [ 285 ] : c = D e /Cl t F τ [h] C/D low [ng/ml/mg] C/D high [ng/ml/mg] Reference Anticonvulsant drugs Mood stabilizers Carbamazepine n. r SPC Felbamate [ 556 ] Lamotrigine [ 118 ] Levetiracetam [ 535 ] Lithium n. r [ 706 ] Oxcarbazepine [ 319, 694 ] Primidone [ 423 ] Topiramate [ 179 ] Valproic acid [ 682 ] Anxiolytic and hypnotic drugs Alprazolam [ 496, 604 ] Bromazepam [ 352 ] Brotizolam [ 341 ] Buspirone [ 41 ] Clonazepam [ 259 ] Diazepam [ 264 ] Lorazepam [ 266 ] Oxazepam 18 (m) 20 (w) Triazolam [ 263 ] Zaleplon [ 265 ] Zolpidem [ 265 ] Zopiclone [ 411 ] Antidementia drugs Donepezil [ 463 ] Galantamine [ 744 ] Rivastigmine (patch) [ 391 ] Drugs for treatment of substance related disorders Acamprosate [ 287 ] Buprenorphin no data available Bupropion [ 665 ] Methadone [ 474,727 ] Naltrexone 6β-naltrexol Varenicline [ 540 ] SPC: Summary of product characteristics; n.r.: not reported; active moiety: risperidone plus 9-hydroxyrisperidone; n: number of individuals; SD: standard deviation Dose related ranges are obtained by multiplying C/D low and C/D high by the dose. Drugs listed in Table 5 were not included in this table, when clearance data were not available from the literature. Prepared by EH and CG, reviewed and supplemented by CH [ 260 ] [ 182 ] from clinical trials of the drug, a dose related reference range can be calculated [285 ]. Definition The dose-related reference range reported in the present guidelines is calculated as a concentration range within that a drug concentration is expected according to pharmacokinetic studies in human blood specimens from subjects under medi cation with a given dose of the drug. It contains 68 % of all the drug concentrations determined under normal conditions in the blood of a normal patient or subject, normal being defined by the population in the respective clinical trial. It usually consists of individuals years of age without relevant comorbidity, comedication, and genetic abnormalities in drug metabolism. For psychoactive medications, such data are available from studies in which drug concentrations were measured in plasma of healthy volunteers or patients treated with fixed doses. When the clearance is taken as arithmetic mean ± standard deviation Table 4 lists factors for calculation of dose-related reference ranges for the most relevant psychoactive drugs. Dose-related reference ranges are calculated by multiplying C/D low and C/D high

10 204 Review by the daily dose. One must be aware, however, that many patients encountered in the clinical context do not fulfil all the abovementioned conditions. Drug concentration in blood and brain The pharmacological activity of a psychotropic drug depends on its availability in the target organ, the brain. However, the latter is separated from the blood by 2 barriers, which have to be crossed by the drug, the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier [154 ]. Most psychoactive drugs enter the brain due to their high lipid solubility by passive diffusion and thereby cross the barriers. The BBB is a physical barrier that separates circulating blood and the central nervous system, and it consists of endothelial cells around the capillaries joined together by tight junctions [154 ]. It efficiently restricts the exchange of solutes between the blood and the brain extracellular fluid. Functionally, it protects the brain against potentially harmful chemicals. As mentioned above, a number of psychoactive drugs, such as risperidone, aripiprazole or venlafaxine are substrates of P-gp [180, 370, 668 ]. As a consequence, brain to plasma concentration ratios vary widely for psychotropic drugs with similar physicochemical properties. Animal studies found ratios from 0.22 for risperidone [ 29 ] to 34 for fluphenazine [ 27 ]. In spite of highly variable ratios of brain to plasma concentrations of the different psychotropic drugs, animal studies have shown that steady-state plasma concentrations of psychoactive drugs correlate well with concentrations in brain, much better than doses. This has been shown for tricyclic antidepressants [ 249 ], trazodone [ 173 ], or olanzapine [ 28 ]. Drug concentrations in plasma can therefore be considered as a valid surrogate marker of concentrations in brain. Drug concentration in blood and target structure occupancy in brain Positron emission tomography (PET) enables analysis of central nervous receptor occupancy in vivo [207, 274, 275 ]. Antipsychotic drugs exert most of their therapeutic actions by blockade of dopamine D2-like receptors. Blockade of D2 receptors by antipsychotic drugs reduces the binding of radioactive PET ligands [207, 272, 275 ]. Using this approach and quantification of the displacement of dopamine receptor radioligands, it has been shown that plasma concentrations of antipsychotic drugs correlate well with receptor occupancy. In accordance with the high variability of drug concentrations in plasma under same doses it was found that receptor occupancy correlates better with plasma concentrations than with daily doses [ 313 ]. Optimal response was seen at % receptor occupancy, and 80 % receptor occupancy was defined as the threshold for the occurrence of extrapyramidal side effects [207, 480 ]. PET was also used to characterize in vivo serotonin transporter occupancy by SSRIs [442, 443 ]. Using a serotonin transporter radioligand, plasma concentrations of citalopram, paroxetine, fluoxetine and sertraline were shown to correlate well with serotonin transporter occupancy. It was found that at least 80 % occupancy should be attained for optimal clinical outcome [442, 443 ]. PET studies have thus brought about highly relevant information for the determination of optimal plasma concentrations of a considerable number of psychotropic drugs which is reviewed in this special issue by Gründer and co-workers [ 274 ]. Therapeutic window therapeutic reference range TDM is based on the assumption that there is a relationship between plasma concentrations and clinical effects (therapeutic improvement, side effects and adverse effects). It also assumes that there is a plasma concentration range of the drug which is characterized by maximal effectiveness and maximal safety, the so-called therapeutic window. Studies on relations between plasma concentration and clinical improvement have supported this concept since the sixties for lithium, tricyclic antidepressants and classical antipsychotic drugs. Systematic reviews and meta-analyses that were based on adequately designed studies led to convincing evidence of a significant relationship between clinical outcomes and plasma concentrations for nortriptyline, imipramine and desipramine which are associated with a high probability of response [ 51 ]. For amitriptyline as a model compound, a meta-analysis of 45 studies has shown that various statistical approaches provided almost identical results [672, 674 ]. For new antipsychotic drugs like aripiprazole [ 612 ], olanzapine [509 ] or risperidone [737 ] relationships between plasma concentration and clinical effectiveness have been reported. For the therapeutic window there are many synonymous terms like therapeutic reference range, therapeutic range, optimal plasma concentration, effective plasma concentration, target range, target concentration, or orienting therapeutic range, the term used in the first consensus [51 ]. The present consensus uses the term therapeutic reference range in accordance with the guidelines on TDM for antiepileptic drugs [ 499 ]. The therapeutic reference range was defined in this consensus guideline for neuropsychiatric drugs as follows: Definition The therapeutic reference ranges reported in this guideline ( Table 5 ) define ranges of medication concentrations which specify a lower limit below which a drug induced therapeutic response is relatively unlikely to occur and an upper limit above which tolerability decreases or above which it is relatively unlikely that therapeutic improvement may be still enhanced. The therapeutic reference range is an orienting, population based range which may not necessarily be applicable to all patients. Individual patients may show optimal therapeutic response under a drug concentration that differs from the therapeutic reference range. Ultimately, psycho pharmacotherapy can be best guided by identification of the patient s individual therapeutic concentration. The therapeutic reference ranges as recommended by the TDM group of the AGNP are given in Table 5. They were evidencebased and derived from the literature by the structured review process described above. For only 15 neuropsychiatric drugs therapeutic reference ranges based on randomized clinical trials were found in the literature. For most drugs, reference ranges were obtained from studies with therapeutically effective doses. Therefore, there is a need for further studies to define therapeutic ranges. The reference ranges listed in Table 5 are generally those for the primary indication. A number of drugs, however, are recommended for several indications. For example, antidepressant drugs are also used for the treatment of anxiety states, and antipsychotic drugs are increasingly used to treat mania. Little information is available on optimum plasma concentrations in these situations. Exceptions are carbamazepine, lamotrigine and

11 205 Table 5 Recommended reference ranges, laboratory alert levels and levels of recommendation for TDM. Drugs and active metabolites Therapeutic reference range/recommended drug concentration t1/2 Laboratory alert level Level of recommendation to use TDM (consensus) Conversion Reference Comments factor (CF, see below) Antidepressant drugs Agomelatine ng/ml 1 2 h after 50 mg Amitriptyline plus nortriptyline Bupropion plus hydroxybupropion ng/ml h 30 h ng/ml 8 26 h h 1 2 h 600 ng/ml [78 ] Because of rapid elimination, trough drug concentrations are not measurable under chronic treatment. Determinations, preferentially of Cmax, should be restricted to specific indications. 300 ng/ml ng/ml [ 282, 502, 672 ] Citalopram ng/ml 33 h 220 ng/ml [ 42, 73, 111, 339, 388, 442, 471, 491, 549, 598 ] Clomipramine plus norclomipramine ng/ml h 36 h 450 ng/ml [ 151, 152, 336, 529, 636] Bupropion, and to a lesser degree its metabolite, are unstable, plasma or serum must be stored frozen ( 20 o C) [ 239 ] N-Demethylated metabolites do not contribute to pharmacological actions Desipramine ng/ml h 300 ng/ml [ 502 ] Delayed elimination in PM of CYP2D6 Desvenlafaxine ng/ml 11 h 600 ng/ml [ 520 ] Dosulepin = Dothiepin ng/ml h 200 ng/ml [ 102, 325, 414, 541 ] Doxepin plus nordoxepin ng/ml h 300 ng/ml [ 172, 321, 393, 445 ] Duloxetine ng/ml 9 19 h 240 ng/ml [ 21, 640, 703 ] No active metabolites Escitalopram ng/ml 30 h 160 ng/ml [ 409, 679 ] N-Demethylated metabolites do not contribute to pharmacological actions lower level of the reference range was calculated from a PET study (80 % 5HTT occupancy) [ 409 ], upper level from the SPC Fluoxetine plus ng/ml 4 6 days ng/ml [ 84, 187, 410, 442, 545 ] Long elimination half life of norfluoxetine (mean 14 days) and norfluoxetine 4 16 days 3.39 long-lasting potent inhibition of CYP2D6 Fluvoxamine ng/ml 20 h 500 ng/ml [ 353, 587, 631, 634, 639 ] Inhibtion of CYP1A2, CYP2C19 [ 72, 229, 245, 510, 538 ] Hydroxylated metabolites Imipramine plus desipramine ng/ml h h 300 ng/ml Maprotiline ng/ml h 220 ng/ml [ 231, 321, 384 ] Active metabolite N-desmethylmaprotiline Mianserine ng/ml h 140 ng/ml [ 191, 192, 453 ] Milnacipran ng/ml 5 8 h 220 ng/ml [ 206, 315 ] Mirtazapine ng/ml h 160 ng/ml [ 257, 367, 397, N-Demethylated metabolite does not contribute to 440, 552, 591 ] pharmacological actions Moclobemide ng/ml 2 7 h ng/ml [ 225, 291, 327 ] Metabolites are pharmacologically inactive Nortriptyline ng/ml 30 h 300 ng/ml [ 30, 31, 504, 506, 510 ] Hydroxylated metabolites Paroxetine ng/ml h 240 ng/ml [ 242, 243, 410, 443 ] Reboxetine ng/ml h 700 ng/ml [ 483, 484 ] Sertraline ng/ml 26 h 300 ng/ml [ 15, 49, 258, 281, 410, N-Demethylated metabolite has a 2-fold longer elimination half life 443, 545, 696 ] than sertraline, but only 1/20 of the activity of sertraline Tranylcypromin 50 ng/ml 1 3 h 100 ng/ml [ 103, 329 ] Due to irreversible inhibition of monoamine oxidase, plasma concentrations do not correlate with drug actions Trazodone ng/ml 4 11 h ng/ml [ 250, 262, 268, 447, 590 ] Trimipramine ng/ml 23 h 600 ng/ml [ 142, 187, 223, 326 ] Active metabolite N-desmethyltrimipramine Venlafaxine plus O- desmethylvenlafaxine ng/ml 5 h 11 h 800 ng/ml Plasma concentrations given in mass units can be converted to molar units by multiplication with the conversion factor (CF) nmol/l = ng/ml x CF & Active metabolite contributes to wanted and unwanted effects. Indicated reference ranges and laboratory alert levels refer to the mother compound only. For bupropion, carbamazepine, lamotrigine and valproic acid recommended reference ranges were listed twice in accordance with the 2 different indications. Prepared by CH, PB, SU, BR and HK, reviewed by AC, OD, KE, MF, MG, CG, GG, EH, UH-R, CH, EJS, HK, GL, UL, TM, BP, BS, MU, SU, GZ [ 85, 241, 316, 443, 545, 550, 592, 684, 696 ] In most patients O-desmethylvenlafaxine is the active principle in vivo, N-demethylated venlafaxine does not contribute to pharmacological actions. At low concentrations, the drug acts predominanty as an SSRI

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